Myers E, Hill A D K, Kelly G, McDermott E W, O'Higgins N J, Young L S
School of Medicine and Medical Science, Saint Vincent's University Hospital, Dublin, Ireland.
Br J Cancer. 2006 Nov 20;95(10):1404-9. doi: 10.1038/sj.bjc.6603427. Epub 2006 Oct 24.
Overexpression of HER2 is associated with an adverse prognosis in breast cancer. Despite this, the mechanism of its transcriptional regulation remains poorly understood. PEA3, a MAP kinase (MAPK)-activated member of the Ets transcription factor family has been implicated in the transcriptional regulation of HER2. The direction of its modulation remains controversial. We assessed relative levels of PEA3 expression and DNA binding in primary breast cultures derived from patient tumours (n=18) in the presence of an activated MAPK pathway using Western blotting and shift analysis. Expression of PEA3 in breast tumours from patients of known HER2 status (n=107) was examined by immunohistochemistry. In primary breast cancer cell cultures, growth factors induced interaction between PEA3 and its DNA response element. Upregulation of PEA3 expression in the presence of growth factors associated with HER2 positivity and axillary lymph node metastasis (P=0.034 and 0.049, respectively). PEA3 expression in breast cancer tissue associated with reduced disease-free survival (P<0.001), Grade III tumours (P<0.0001) and axillary lymph node metastasis (P=0.026). Co-expression of PEA3 and HER2 significantly associated with rate of recurrence compared to patients who expressed HER2 alone (P=0.0039). These data support a positive role for PEA3 in HER2-mediated oncogenesis in breast cancer.
HER2的过表达与乳腺癌的不良预后相关。尽管如此，其转录调控机制仍知之甚少。PEA3是Ets转录因子家族中一种丝裂原活化蛋白激酶（MAPK）激活的成员，已被证明与HER2的转录调控有关。其调节方向仍存在争议。我们使用蛋白质免疫印迹法和迁移分析，评估了来自患者肿瘤的原代乳腺培养物（n = 18）在存在激活的MAPK途径时PEA3的相对表达水平和DNA结合情况。通过免疫组织化学检查了已知HER2状态的患者（n = 107）乳腺肿瘤中PEA3的表达。在原发性乳腺癌细胞培养物中，生长因子诱导PEA3与其DNA反应元件之间的相互作用。在与HER2阳性和腋窝淋巴结转移相关的生长因子存在的情况下，PEA3表达上调（分别为P = 0.034和0.049）。乳腺癌组织中PEA3的表达与无病生存期缩短（P < 0.001）、III级肿瘤（P < 0.0001）和腋窝淋巴结转移（P = 0.026）相关。与仅表达HER2的患者相比，PEA3和HER2的共表达与复发率显著相关（P = 0.0039）。这些数据支持PEA3在HER2介导的乳腺癌肿瘤发生中起积极作用。
